Constrained by in vivo biological transport capability of a drug itself, it must be transported to its targets in focal tissues, focal cells and its subcellular organelles through systemic circulation depending on its physico-chemical properties to perform its efficacy. However, according to biopharmaceutics and pharmacokinetics characteristics of the existing drugs, obviously they are in lack of specificity to pathological tissue and healthy tissue. A higher dose of drug is required to achieve a satisfactory curative effect, which is prone to cause occurrence of drug toxicity/side effects, and thereby confines the clinical application of the drugs.
Targeted therapy is one of the most effective measures to solve the problems described above. Molecular targets of the drugs are mainly concentrated in cells of focal tissues, wherein enzymes account for 50%, receptors account for 35%, and ion channels account for 15%. The curative effects of the drugs are primarily implemented through occupied effect on molecular targets. For instance, the majority of molecular targets of cytotoxic anticancer drugs are DNA mainly located in the nucleus of tumor cells (such as mitomycin C, doxorubicin, camptothecin), or microtubule protein located in cytoplasm (such as paclitaxel, vinblastine). Molecular targets of gene therapy drugs are also located in the cytoplasm or nucleus of target cells, such as plasmid DNA in the nucleus, and siRNA in the cytoplasm. Molecular targets of antiviral drugs are also located in the nucleus or cytoplasm of target cells. To target a drug directly to pathological tissues (organs) and cells through an appropriate carrier technology is one of the important means to resolve the problems of low efficacy and toxicity/side effects. Currently, certain progress on targeting the antitumor drugs to tissue (organ) and cell has been made at home and abroad by carrier technologies, but no breakthrough of a curative effect has been obtained. The essence of the problem is that vast majority of molecular targets for anticancer drugs are located within cells. Therefore, research and development on the materials of drug carriers targeting to molecular target points (subcellular organelles) within tumor cells is the key to break the bottleneck of cancer chemotherapy.
Design of a targeting carrier is mainly involved in targeting effect of the carrier to focal organs and targeting effect of focal cells across focal organs based thereon, so as to achieve the targeting effect to subcellular organelles for a drug molecular target. In the early targeting of drugs to tissues and organs, a small particle size of particulates is used to passive target to organs, such as liver, and a concentration on tumor tissues is achieved through an enhanced permeability and retention effect.
Currently, based on overexpression characteristics of certain receptors on tumor cell surface (such as the folate receptor), ligand-modified carrier materials have been successfully applied in targeted cancer therapy to achieve targeting to tumor cells, improve the intracellular concentration of anticancer drugs and enhance the efficacy of anticancer drugs themselves. Recently, polymer micelles have attracted an extensive attention in the fields of pharmaceutics, and biomedicine. Polymer micelles are formed of amphiphilic block copolymers or graft copolymers in an aqueous media by self-assembly, and have a core-shell structure. In the polymer micelle, hydrophobic segments and hydrophilic segments form the core and shell of the micelle, respectively. The hydrophobic core can serve as a poorly water soluble drug. The outer hydrophilic membrane maintains stability of the micelle in an aqueous environment, and may modify the physical and chemical properties to achieve particular purposes, such as, active targeting effect of the micelle.
The polymer micelle as a drug delivery system has many advantages. It can control in vivo release of drugs by regulating properties of the material, such as, solubility, pH value, zeta potential and the like. Since the particle size of the micelle is rather small, it can not only permeate through blood-brain barrier and reticuloendothelial system, but also promote absorption of gastrointestinal mucosa and the like, so as to reach the location where large-size particles can not pass through, thereby achieving the purpose of a passive targeting. A protection and shielding effect of the polymer micelle skeleton can prevent the drug from being decomposed to some extent, maintain stability of the drug and reduce toxicity of the drug. In comparison to liposomes, drug loading of the polymer micelle is relatively higher. Diversity of the polymer materials is in favor of production of diversified pharmaceutical preparations using the polymer as a carrier, thereby meeting requirements of various applications.
It has been reported that a hydrophilic PEGylation of a drug carrier can reduce both plasma protein adsorption on the carrier and phagocytosis of the drug carrier by macrophage, thereby prolonging half-life of the carrier in the circulatory system. On this basis, a PEGylation of the hydrophilic shell for polymer micelles can reduce opsonification of plasma protein of polymer micelles, thereby reducing the uptake of polymer micelles by macrophage and postponing elimination of polymer micelles from the plasma. The passive targeting of polymer micelles in tumor tissue can be further improved through the enhanced permeability and retention effect. On the other hand, an active targeting to other organs and tissues can be implemented by a ligand- or antibody-modification.
In the present invention, on the basis of our previous study, a fatty acid grafted chitosan oligosaccharide micelle having rapid cellular uptake and organelle targeting effect has been employed to carry out a surface modification with PEG to synthesize a long-circulating fatty acid grafted chitosan oligosaccharide which can avoid identification of reticuloendothelial system. Such a fatty acid grafted chitosan oligosaccharide can be applied to preparation and application of anticancer drugs, gene therapy drugs, antiviral drugs and so on.